AUTHOR=Shin June Ho , Moreno-Nieves Uriel Y. , Zhang Luhua H. , Chen Chen , Dixon Amera L. , Linde Miles H. , Mace Emily M. , Sunwoo John B. 

TITLE=AHR Regulates NK Cell Migration via ASB2–Mediated Ubiquitination of Filamin A

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.624284

DOI=10.3389/fimmu.2021.624284

ISSN=1664-3224

ABSTRACT=<p>Natural killer (NK) cells are effector cells of the innate immune system involved in defense against virus-infected and transformed cells. The effector function of NK cells is linked to their ability to migrate to sites of inflammation or damage. Therefore, understanding the factors regulating NK cell migration is of substantial interest. Here, we show that in the absence of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, NK cells have reduced capacity to migrate and infiltrate tumors <italic>in vivo</italic>. Analysis of differentially expressed genes revealed that ankyrin repeat and SOCS Box containing 2 (<italic>Asb2</italic>) expression was dramatically decreased in <italic>Ahr</italic><sup>–/–</sup> NK cells and that AhR ligands modulated its expression. Further, AhR directly regulated the promoter region of the <italic>Asb2</italic> gene. Similar to what was observed with murine <italic>Ahr</italic><sup>–/–</sup> NK cells, <italic>ASB2</italic> knockdown inhibited the migration of human NK cells. Activation of AHR by its agonist FICZ induced ASB2-dependent filamin A degradation in NK cells; conversely, knockdown of endogenous <italic>ASB2</italic> inhibited filamin A degradation. Reduction of filamin A increased the migration of primary NK cells and restored the invasion capacity of AHR-deficient NK cells. Our study introduces AHR as a new regulator of NK cell migration, through an AHR-ASB2-filamin A axis and provides insight into a potential therapeutic target for NK cell-based immunotherapies.</p>